Hypertension affects approximately 20% of Americans and is associated with approximately 200,000 deaths annually from myocardial infarction, stroke and renal disease and yet, the precise molecular causes of disease are poorly understood. There is increasing epidemiological and experimental evidence that the prenatal administration of glucocorticoids to pregnant mothers increases blood pressure and cardiovascular disease in adult progeny. Unfortunately, the precise molecular determinants of this effect are not understood. Because glucocorticoids cause a wide range of developmental and physiologic effects in disparate tissues, it is not clear which glucocorticoid effect predisposes to hypertension. There is, at present, no method to experimentally target glucocorticoids to specific tissues in the developing fetus, and thus, distinguishing primary glucocorticoid effects from secondary sequelae has not been possible. In the course of studies to understand precise structural determinants of steroid hormone receptor function, we have generated a mutant glucocorticoid receptor with enhanced sensitivity to glucocorticoids. In this proposal, we will take advantage of recent advances in recombinant mouse genetics to create a gain-of-function GR knock-in mouse, which will allow us to assess the effects of glucocorticoid expression in individual tissues, and thereby gain insight into fundamental mechanisms of hypertension.